This competing continuation application (R01 DA002519) is designed to identify and evaluate potential treatment medications for cocaine abuse and dependence. Cocaine abuse remains a significant public health problem that afflicts an estimated 5 million Americans and over 16 million persons worldwide. There is no uniformly effective FDA-approved medication for cocaine abuse treatment, and this continues to be a high priority area. On the basis of our discoveries during the past project period, we propose to examine some potential treatment medications approved by the FDA for another indication, as well as novel approaches that may suggest new directions for medications development. In translational studies, we reported that buspirone and modafinil significantly and selectively decreased cocaine self-administration by rhesus monkeys (See Preliminary Studies). We now propose to evaluate modifications of these clinically available medications that may be more effective than the parent compounds due to longer duration of action and an improved safety profile (lower potential for abuse or dependence). Buspirone's active metabolites (5-OH and 6-OH buspirone) have dopamine D3 and D4 receptor activity that may account for buspirone's reduction of cocaine self-administration. Armodafinil, the R- enantiomer of modafinil, is longer acting, effective at lower doses and likely to have low abuse potential. A second focus of our proposed research is to continue to examine how monoaminergic ligands modulate the abuse-related effects of cocaine. We hypothesize that novel combinations of norepinephrine + serotonin releasers and dopamine releasers + serotonin reuptake inhibitors may selectively reduce cocaine self-administration with minimal abuse liability and side effects. We discovered that acute administration of a 5-HT2C agonist and a 5-HT2A antagonist each significantly and selectively reduced cocaine self-administration by rhesus monkeys (see Preliminary Studies). We propose to study the effects of chronic treatment with these serotonergic compounds on the abuse-related effects of cocaine. We hypothesize that combining low doses of 5-HT2C and 5-HT2A compounds will have synergistic effects on cocaine self-administration and reinstatement in rhesus monkeys. Well-validated behavioral procedures (drug self-administration, drug-, cue-, and stress-induced reinstatement, and drug discrimination) will be used to evaluate candidate medications in a nonhuman primate model of cocaine addiction. The neurobiology, neurochemistry and neuroanatomy of rhesus monkeys is very similar to humans, and there is good correspondence between preclinical and clinical evaluations of medication effects on several aspects of cocaine addiction. These preclinical models of cocaine addiction are essential for guiding decisions about development of novel medications for clinical treatment. The overall goal of the proposed research is to discover more effective medications for the treatment of cocaine abuse.